The clinical utility of rapid exome sequencing in a consanguineous population
Authors: Dorota Monies, Ewa Goljan, Abdulaziz Mohammed Binmanee, Abdullah Ali Zafir Alashwal, Abdullah Mohammed Alsonbul, Abdulrahman A. Alhussaini, Alahmari Ali Abdallah, Ali Hussain Albenmousa, Ali Ibrahim Almehaidib, Ali Syed Akhtarul Hassan, Amal Salman Alseraihy Alharbi, Amro Alhabib, Antonello Podda, Badr Alsaleem, Bandar Bin Khalid Al Saud, Bassam Saleh Bin Abbas, Eissa Ali Faqeih, Fahad Badei Aljofan, Fahad Naser Alhazzani, Fouzah Awadh Alrowaily, Hamad Ibrahim Alzaidan, Hamoud Abdulkareem Almousa, Hawazen Saleh Alsaedi, Ibrahim Abdulaziz Ghemlas, Khalid Abdulrahman Alsaleem, Mahasen Saleh, Malak Alghamdi, Marwa Shams, Moath Alabdulsalam, Mohamed Salaheldin Bayoumy, Mohammad Ali Shagrani, Mohammed Abdulaziz Alowain, Mouhab Fakhreddine Ayas, Muhammad Qasim, Muneera J. Alshammari, Najeeb Shafat Qadi, Ohoud Saleh Alzahrani, Rand K. H. Arnaout, Reem Alhamad, Reem Walid Mohammed, Ruqaiah Saleh Altassan, Saad Ali Alghamdi, Saadiya Javed Khan, Saleh Abdulrahman Alalaiyan, Sameena Khan, Sultan Ibrahim Albuhairi, Talal Turki Algoufi, Tareq Mohammed Alayed, Tari Alofisan, Wajeeh Mohamed Aldekhail, Waleed Alhamoudi, Wesam Ibrahim Yousef Kurdi, Zuhair Abdalla Rahbeeni, Mirna Assoum, Muna Albreacan, Faisal Binhumaid, Shazia Subhani, Abdulmlik Boureggah, Mais Hashem, Firdous Abdulwahab, Omar Abuyousef, Mohamad H. Temsah, Fahad Alsohime, James Kelaher, Mohamed Abouelhoda, Brian F. Meyer, Fowzan S. Alkuraya
Journal: Genome Medicine (2023)

Abstract Background The clinical utility of exome sequencing is now well documented. Rapid exome sequencing (RES) is more resource-intensive than regular exome sequencing and is typically employed in specialized clinical settings wherein urgent molecular diagnosis is thought to influence acute management. Studies on the clinical utility of RES have been largely limited to outbred populations. Methods Here, we describe our experience with rapid exome sequencing (RES) in a highly consanguineous population. Clinical settings included intensive care units, prenatal cases approaching the legal cutoff for termination, and urgent transplant decisions. Results A positive molecular finding (a pathogenic or likely pathogenic variant that explains the phenotype) was observed in 80 of 189 cases (42%), while 15 (8%) and 94 (50%) received ambiguous (variant of uncertain significance (VUS)) and negative results, respectively. The consanguineous nature of the study population gave us an opportunity to observe highly unusual and severe phenotypic expressions of previously reported genes. Clinical utility was observed in nearly all (79/80) cases with positive molecular findings and included management decisions, prognostication, and reproductive counseling. Reproductive counseling is a particularly important utility in this population where the overwhelming majority (86%) of identified variants are autosomal recessive, which are more actionable in this regard than the de novo variants typically reported by RES elsewhere. Indeed, our cost-effectiveness analysis shows compelling cost savings in the study population. Conclusions This work expands the diversity of environments in which RES has a demonstrable clinical utility.